Boron neutron capture therapy carboranes

Yinghuai Z, Peng AT, Carpenter K, Maguire JA, Hosmane NS, Takagaki M (2005) Substituted carborane-appended water-soluble single-wall carbon nanotubes New approach to boron neutron capture therapy drug delivery. J. Am. Chem. Soc. 127 9875-9880. 

Like PAMAM dendrimers, polylysine dendrimers are largely characterised by amide bonds. They attracted interest as potential therapeutic agents for use in boron neutron capture therapy and in magnetic resonance imaging (MRI) (see Chapter 8), since dendritic polylysines apparently have a lower toxicity than their linear counterparts. The polylysine shown in Fig. 4.10 with a total of 80 terminal boron atoms in the carborane units and a dansyl group was designed specifically for boron neutron capture therapy [20]. 

Scheme 5.7. Synthesis of water soluble o-carboranes for investigation as Boron Neutron Capture Therapy reagents.

Polyols of a cascade type as a water-solubilizing element of carborane derivatives for boron neutron capture therapy. [H. Nemoto, J. G. Wilson, H. Nakamura, Y. Yamamoto, J. Org. Chem. 1992, 57, 435-435] [ 811]. 

Carboranes, at a first glance at least exotic for biological applications (apart from boron neutron capture therapy), have become a fundamental class of chelators for organometallic radiopharmaceuticals. Their preparation, derivatization, and conjugation have reached a level of routine feasibility and they merit broader attention concerning classes of targeting molecules. The combination of molecular imaging opportunities with heavily boron-loaded compounds will allow to quantify the accumulation of boron clusters as a base for improved boron neutron capture therapy. 

The rapid development of carborane chemistry is mainly due to their practical applications. For instance, the potential utility of carborane polymers as gaskets, O-rings, and electrical connector inserts has been reported. Their functionality for solvent extraction of radionuchdes as well as the potential medicinal value of the isoelectronic and isostructural boron analogues of biologically important molecules has been the subject of many review articles. For example, a number of boron compounds have been found to possess anti-inflammatory and antiarthritic activity in animal model studies. Boron compounds have also been implicated in studies designed to probe the importance of the so-called anionic subsite of acetylcholine esterase and Ach receptors. But, by far the most interesting practical apphcations of carboranes are in areas of boron neutron capture therapy (BNCT) and supramolecular assembly. 

Carboranes in Boron Neutron Capture Therapy of Cancer (B7YC2). The stable isotope of boron, B (19.8% natural abundance), is very effective as a neutron capture agent with the effective nuclear cross section of 3837 bams, while the "B nucleus is incapable of undergoing a BNC reaction. Therefore, the B-emiched carborane and borane-substituted biomolecules and dmgs are selectively dehvered to the cancer cells in the human body and then the tumor-localized B nucleii are bombarded with either thermal or epithermal neutrons that results in a fission reaction producing the high energy alpha (a) particles as shown in equation (2). 

Kane, R.R. Drechsel, K. Hawthorne, M.F. Automated synthesis of carborane-derived homogeneous oligophosphates Reagents for use in the immunoprotein-mediated boron neutron capture therapy (BNCT) of cancer. J. Am. Chem. Soc., 115, 8853-8854, 1993. 

Carboranes are particular cyclic spacers that have been introduced for boron neutron capture therapy to be taken up by tumor cells [295,296,297]. Aromatic spacers have been integrated in cyclodextrin analogues to modify the guest binding properties [298,299,300]. Also amide-linked polymeric open chain sugars with aromatic spacers were prepared [257,264,301]. Sugars with cyclic spacers are also found in Nature [302], well known examples are antibiotics such as calicheamicin [303,304] or vancomicin [305]. 

A new series of 5-carboranyl-substituted-2 -deoxyuridine (25a) and deoxy-thymidine (25b) derivatives containing a range of alkyl spacers has been prepared to access a more effective use of boron neutron capture therapy. Evaluation of these derivatives as substrates for the human thymidine kinases TKl and TK2 showed that a decrease in the length of the spacer (from 8 methylene units to 4) between the carborane moiety and the pyrimidine base resulted in better substrate characteristics. 

Most of the known Cr hydride complexes are the 7r-donor, sandwich-type carborane complexes,676,677 which are described in the Comprehensive Organometallic Chemistry series. Recently, a pendant-arm Cr111 carborane complex containing a pyridine donor (143) has been prepared and characterized by spectroscopic methods.678 Complexes of this type are of interest in the synthesis of new compounds for the treatment of cancer by boron neutron capture therapy and the development of new catalytic systems for alkene polymerization (Section 4.6.5.1.2).678... 

Carboranes - polyhedral boranes containing carbon in the framework - have been known for over 35 years, and their intrinsic stability, versatility, structural variety, and electronic properties have been put to use in a number of diverse areas, [1] for example in the synthesis of extraordinarily heat-stable polymers, in BNCT (boron neutron capture therapy), as ligands in metallacarborane catalysts, as com-plexing agents for extraction of metal ions, as precursors to ceramics, conducting polymers, and nonlinear optical materials, as anticancer... 

In present report we developed new approaches to the synthesis of C- and B-organylsubstituted carboranes using both metallation and cross-coupling reactions, that are of doubtless interest for investigations in the field of Boron Neutron Capture Therapy. 

The. synthesis of oligonucleotides which are derivatised with carboranes are of potential use in boron neutron-capture therapy. Thymidine(3, 5 )thymidine(0-carhoran-l-ylmethyl)phosphonate (128) has been prepared via synthesis of the borophosphonylating agent 5 -0-(monomethoxytrityl)thymidine 3 -0-[methyl (O-carboran-l-ylmethyl)phosphonate]. ... 

Di Meo C, Panza L, Capitani D, Mannina L, Banzato A, Rondina M, Renier D, Rosato A, Crescenzi V. Hyaluronan as carrier of carboranes for tumor targeting in boron neutron capture therapy. Biomacromolecules 2007 ... 

Altieri, S., M. Balzi, S. Bortolussi, P. Bruschi, L. Ciani, A. M. Clerici, P. Faraoni, C. Eerrari, M. A. Gadan, L. Panza, D. Pietrangeli, G. Ricciardi, and S. Ristori. 2009. Carborane derivatives loaded into liposomes as efficient delivery systems for boron neutron capture therapy. J. Med. Chem. 52 7829-7835. 

An alternative approach explored functionalization of SWNT with substituted car-borane cages to develop a new delivery system for an efficient boron neutron capture therapy [54]. Indeed, these studies showed that some specific tissues contained carbor-ane following intravenous administration of the CNT conjugate and, more interestingly, that carborane was concentrated mainly at the tumor site. 

The incorporation of a large number of boron atoms into a tumor for boron neutron capture therapy (BNCT) has been accorded considerable interest over the last few years [67]. It is known that if boron-containing cells are exposed to a neutron flux, they are destroyed without causing irreparable harm to adjacent healthy tissue. In the context of SERMs, for example, Endo et al. have prepared complex 18 [ 1 - (hydroxymethyl) -12- (4-hydroxyphenyl) -1,12-dicarba-closo-dodeca-borane] in which the hydrophobic carborane cage mimics the C and D rings of estradiol (Scheme 3.7) [68]. 

Synthesis and Characterization of Carborane Functionalized Dendronized Polymers as Potential Boron Neutron Capture Therapy Agents... 

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